title: Mapping of allosteric druggable sites in activation-associated conformers of the M2 muscarinic receptor.
abstract: G-protein-coupled receptors (GPCRs) are key cellular signaling proteins and have been targeted by approximately 30-40% of marketed drugs for treating many human diseases including cancer and heart failure. Recently, we directly observed activation of the M2 muscarinic receptor through long-timescale accelerated molecular dynamics (aMD) simulation, which revealed distinct inactive, intermediate and active conformers of the receptor. Here, FTMAP is applied to search for 'hot spots' in these activation-associated conformers using a library of 16 organic probe molecules that represent fragments of potential drugs. Seven allosteric (non-orthosteric) binding sites are identified in the M2 receptor through the FTMAP analysis. These sites are distributed in the solvent-exposed extracellular and intracellular mouth regions, as well as the lipid-exposed pockets formed by the transmembrane α helices TM3-TM4, TM5-TM6 and TM7-TM1/TM2. They serve as promising target sites for designing novel allosteric modulators as receptor-selective drugs.
authors.affiliation: Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA, 92093, USA.
authors.forename: Yinglong
authors.initials: Y
authors.lastname: Miao
authors.forename: Sara E
authors.initials: SE
authors.lastname: Nichols
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D000495:Allosteric Site; D001665:Binding Sites; D006801:Humans; D056004:Molecular Dynamics Simulation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D043585:Receptor, Muscarinic M2 / Q000737:chemistry* / Q000378:metabolism; D012997:Solvents / Q000737:chemistry
chemical_list: D043585:Receptor, Muscarinic M2; D012997:Solvents
keywords: FTMAP; GPCR; M2 muscarinic receptor; accelerated molecular dynamics; allosteric sites; receptor-selective drugs